Glycogen synthase kinase-3β (GSK3β) expression in a mouse model of Alzheimer's disease: a light and electron...

Glycogen synthase kinase-3β (GSK3β) activity has been previously linked to Alzheimer's disease (AD) by its phosphorylation of tau and activation by amyloid. GSK3β intracellular distribution is important in regulating its activity by restricting access to compartment-specific substrates. This study investigated regional and intracellular distribution of GSK3β in a mouse model of AD, a bigenic mouse with combined amyloid and tau pathology (BiAT), and controls (FVB). At two different ages, the entire rostrocaudal extent of each brain was examined. Young (6-months-old) FVB and BiAT mice did not differ in GSK3β expression and localization. In old (13-month-old) BiAT mice, neurons showed increased GSK3β expression only in AD-relevant brain regions as compared with modest staining in region- and age-matched controls. Two regions with the most robust changes between FVB and BiAT mice, the amygdala and piriform cortex, were quantified at the light microscopic level. In both regions, the density of darkly labeled neurons was significantly greater in the old BiAT mice vs. the old FVB mice. Electron microscopy of the piriform cortex showed neuronal GSK3β labeling in the rough endoplasmic reticulum, on ribosomes, and on microtubules in dendrites in both strains of mice. In old BiAT mice, GSK3β labeling was qualitatively more robust compared to age-matched controls, and GSK3β also appeared in neurofibrillary tangles. In conclusion, GSK3β expression was increased in specific intracellular locations and was found in tangles in old BiAT mice, suggesting that GSK3β overexpression in specific brain areas may be intrinsic to AD pathology.